PROJECT SUMMARY: Peri-infarct depolarizations (PIDs) are a promising therapeutic target in stroke and other brain injury states because they frequently occur after brain injuries and negatively impact tissue vitality by inducing pronounced change in hemodynamics. Although PIDs that occurred over chronic time scales were confirmed to lead to neuronal deterioration in patients, most animal studies are limited at the acute phase for up to a few hours post occlusions, largely due to a lack of methods capable of simultaneously quantifying neurophysiological and hemodynamic parameters with sufficient spatial resolution over periods of weeks to months. As a result, the hemodynamic and neural consequences of chronically occurred PIDs remains poorly understood, limiting the ability to clearly target them to optimize and tailor intervention strategies. The objective of this project is to provide systematic characterization of PIDs in a mouse stroke model by spatially resolving and mapping of hemodynamics and neural activity from acute to chronic time scales and at controlled infarction size. The hypothesis is that such systematic characterization of PIDs will be enabled by developing a chronically viable, multimodal platform that integrates high-resolution functional optical imaging of hemodynamics and targeted photothrombosis with spatially resolved electrical recording of neural activity. We will use two types of ultra- flexible nanoelectronic neural probes for different detection ranges and resolutions, both of which are compatible with chronic optical methods. We will employ a novel optical system combining multi-exposure speckle imaging and phosphorescence lifetime quenching to simultaneously image and quantify cerebral blood flow and oxygen tension chronically, which also enables targeted photothrombosis with fine control over the lesion location and size. We will pursue the following aims: 1: Characterize and optimize the multi-modal platform for acute and chronic studies at awake. 2: Determine the chronic consequences of PIDs on hemodynamics and neural activity, including to quantify and spatially map the hemodynamic consequence of chronic occurring PIDs, and to determine the cortical-depth and lesion-size dependence of PID characteristics. The application is highly innovative, in the applicant?s opinion, because it integrated technical advancements at multiple fronts to provide a highly novel and powerful combination that permits studies of PIDs in previously unattainable temporal and spatial regimes. The application is significant, because it is expected to vertical advance the fundamental understanding the induction and consequences of PIDs, and to have broad translational importance in the intervention of a number of neurological conditions where PIDs are known to occur. The long-term goal of this project is to quantify the risk of PIDs with extreme variability in the size, location, severity, and mechanism similar to those occurred in human strokes in order to develop and optimize intervention strategy and improve tissue outcome after stroke.